Angiotensin-converting enzyme (ACE) inhibitors reduce mortality in hypertension, heart disease and diabetes. Although generally safe, ACE inhibitors rarely cause angioedema, which can result in hospitalization, intubation or tracheotomy, and even death. Identifying those at increased risk for serious adverse events such as angioedema can inform future drug development. Over the last 5 years, our group has identified one biochemical mechanism underlying ACE inhibitor associated- angioedema, that of dipeptidyl peptidase IV (DPPIV) deficiency. DPPIV, a cell-surface protease, preferentially cleaves dipeptides from the amino terminus of peptides with a penultimate proline or alanine, including the incretins, vasoactive peptides such as substance P, and cytokines. We have found that serum DPPIV antigen and activity are decreased in patients with ACE inhibitor-associated angioedema. During ACE inhibition, the degradation half-life of substance P in plasma correlates inversely with DPPIV antigen. Rats deficient in DPPIV exhibit increased sensitivity to ACE inhibitor- induced peritracheal edema, an effect that is reversed by a substance P (NK1) receptor antagonist. We have identified genetic variants in the gene encoding DPPIV (DPP4) that associate with DPPIV activity and antigen, with ACE inhibitor-associated angioedema in black Americans, a group at increased risk for angioedema, and with DPPIV activity during pharmacological inhibition. The observation that use of a pharmacological DPPIV inhibitor is associated with angioedema in diabetics taking ACE inhibitors confirms an etiological role of DPPIV deficiency in the pathogenesis of ACE inhibitor-associated angioedema in humans. At the same time, preliminary data suggest that DPPIV inhibition moderates the antihypertensive response to ACE inhibition. During the next period, we will elucidate the interactive effect of DPPIV and ACE inhibition on the degradation of vasoactive peptides in humans (Aim 1). In collaboration with RIKEN and the Pharmacogenetics Research Network, we will use state-of-the art genetic methods in our carefully phenotyped subjects to identify additional genetic variants that predispose individuals to ACE inhibitor-associated angioedema. We will validate the association of these variants with ACE inhibitor-associated angioedema and therapeutic responses in other populations (Aim 2). These studies promise to enhance our understanding of the role of DPPIV in human physiology, to elucidate mechanism(s) underlying the interaction of ACE and DPPIV inhibitors (two classes of drugs likely to be used together with increasing frequency in our growing population of diabetics), and to lead to new approaches to the personalized use of these and related medications.